World wide the prevalence of autoimmune disease is about 3%. Autoimmune diseases can be either organ specific or systemic, but in either case their most notable quality is that their cause is multifactorial, including both genetic and environmental influences. Over the past several years much progress has been made in elucidating underlying genetic lesions associated with autoimmune disease, but surprisingly comparatively little effort has been directed towards understanding the influences of environmental factors. Our long term research goal is to correct this imbalance and further our understanding of the etiology of autoimmune disease by uncovering the mechanisms by which environmental factors, and toxicants in particular, interact with the immune system to promote autoimmune disease. A major problem in this field has been the difficulty in linking exposure to specific environmental factors, especially toxicants, with autoimmune disease. One of the few exceptions is environmental mercury. Accordingly, the focus of this proposal will be on the immunotoxicology of inorganic mercury (Hg2+). In a number of different systems Hg2+ has been shown to promote autoimmune disease. Thus Hg2+ naturally lends itself as a tool with which to probe the environment- autoimmunity axis. Recently there has been renewed interest in the role that B cells play in autoimmune diseases. Preliminary and recently published results from our laboratory support our hypothesis that low and non toxic burdens of Hg2+ <0.01 pg/cell directly impair central tolerance in the B cell compartment by interfering with B Cell Receptor (BCR) signal transduction in immature transitional 1 (T1) B cells. Existing knowledge supports the concept that signal strength through the BCR on T1B cells is a major determinant that shapes the humoral immune repertoire and establishes tolerance to self antigens. Based on our preliminary studies, we propose that BCR signal strength is attenuated by environmentally relevant levels of Hg2+. This proposal will address the global hypothesis that BCR signaling profiles of Hg-exposed versus non-exposed B lymphocytes differ. We plan to employ flow cytometric-based techniques to map signaling networks in individual cells (i.e., single cell proteomics) as well as mass spectrometry based techniques designed to rapidly survey the B cell proteome in Hg-exposed and non-exposed cells. PUBLIC HEALTH RELEVANCE: The etiology of most autoimmune diseases is unknown, but most investigators believe that environmental and genetic factors are involved. While in recent years there has been much progress in understanding the genetic factors involved in autoimmune diseases, there has been much less progress in understanding the impact of environment. The purpose of this research is to investigate how low levels of the environmental toxicant mercury, might interact with the immune system in such a way as to promote autoimmune disease.